The use of psychotropic medications in the elderly population is always challenging due to decreased efficacy and an exacerbated side effects. Thus, there is an urgent need to find new and efficient ways to increase efficacy and to decrease side effects of antipsychotics for aged individuals. Age-related changes epigenetic modulation may contribute to the deterioration of appropriate gene expression induced by antipsychotics. Previous studies have suggested that disruption in receptor functions of dopamine during aging, the primary target of antipsychotic drugs, may be due to changes in gene expression. Age-related changes in the homeostatic tone of the dopaminergic system may be mediated by epigenetic mechanisms, thus revealing a potential reversibility of these effects by pharmacological therapeutic intervention. For this study, we will investigate (1) if age-related decrease of striatal and cortical dopamine 2 (D2) receptor (mRNA and protein levels) are due to histone hypoacetylation and hypermethylation; (2) if increased physiological and behavioral sensitivity to antipsychotic drugs in aged mice is due to decreased D2 gene and protein expression and decreased D2 receptor occupancy and (3) if co-treatment of HDAC inhibitors (valproic acid (VPA) and vorinostat (SAHA)) will decrease haloperidol (HAL)-induced extrapyramidal side effects (EPS) in aged mice by reversing age-related epigenetic effects. Our preliminary findings revealed that co-treatment of HAL with VPA reverses age-related hypoacetylation at the striatal Drd2 promoter region that correlates with decreased D2 receptor protein expression. These changes are associated with decreased HAL-induced EPS behavior. These findings, together with the dissertation proposal, will indicate whether aging reduces histone acetylation and increases histone tri-methylation levels in the striatum and prefrontal cortex that subsequently interfere with the regulation of D2 receptor which is relevant for reduction of EPS. Our study will provide molecular, cellular, pharmacological and behavioral evidence showing that age-related histone modifications affect antipsychotic properties, uncovering the links between aging, epigenetic modulation and antipsychotic drug action. This proposal will help to develop novel therapeutic strategy for aged people, particularly those that suffer from psychiatric disorders.